Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are two signature disorders of Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). The two conditions, which often stem from the same event, are frequently comorbid and present with overlapping symptom profiles (e.g. dysphoria, irritability, impaired concentration, sleep disturbance), and result in significant impairment. However, the persistent symptoms of mTBI (such as postconcussive syndrome) and PTSD vary significantly across individuals, even those exposed to similar trauma, suggesting that individual differences play a substantial role in determining long-term outcomes of trauma exposure. Identifying biological factors that underlie these differences would be a critical step towards identifying personalized and targeted rehabilitative interventions. To date, researchers have identified certain genetic and neural correlates of trauma-related psychopathology, but these findings have limited rehabilitative utility due to 1) the lack of consideration for environmental influences, 2) few genome-wide studies in PTSD and none in TBI, 3) the lack of attention to the polygenic effect of multiple variants, and 4) lack of integration across levels of analysis (i.e. between genetics and neuroimaging). The proposed study will use previously collected data to address these limitations by applying a ?neurogenetic? approach, which models relationships between genes, the environment, and neural sequelae of trauma in OEF/OIF veterans. Specifically, results from an existing PTSD genome-wide association study will be used to generate a polygenic risk score (PGRS), which calculates an individual?s cumulative genetic risk by summing the number of risk alleles across the genome, weighted by each allele?s relative risk. Aim 1 of the proposed study will conduct a GWAS on the previously collected data in order to calculate a PGRS, which will be used along with combat stress (including physiological and psychological traumatic experiences) to form a polygenic gene by environment (PGxE) interaction. This PGxE interaction will then be used to predict the shared symptoms associated with mTBI and PTSD in three independent samples of OEF/OIF veterans, including one consisting exclusively of veterans with a history of mTBI. This would serve as a cross-validation of PTSD genetic risk into an mTBI sample, thus supporting a shared etiological foundation and laying the groundwork for personalized rehabilitative interventions for those who are most at risk. Aim 2 of the proposed study will determine if the PGRS score interacts with combat stress to predict biological intermediate phenotypes associated with trauma-related symptomatology. Specifically, anatomical and functional neural connectivity, measured using diffusion tensor imaging and resting state functional magnetic resonance imaging, will be used as dependent variables in PGxE analyses. These neural indices will then be included in a structural equation model (SEM) to identify any possible mediation of the initial PGxE interaction, which would support a plausible mechanistic pathway by which genetic vulnerability increases risk for abnormal neural connectivity, which increases the probability of trauma-related symptomatology. To our knowledge, the proposed project would be the first to look at genome-wide characterization of TBI patients, to examine polygenic influence on trauma-related symptoms, to model a PGxE interaction, and to apply a neurogenetic approach to identify genetic predictors of neural sequelae to trauma. The results of this project will shed considerable light on the mechanistic pathways that confer risk for trauma-related pathology, allowing for more informed and more personalized applications of rehabilitative strategies.